Background: To improve clinical prospects of patients with locally advanced cutaneous SCC (CSCC), we tested the efficacy of neoadjuvant nivolumab with or without ipilimumab prior to standard of care curative surgery ± radiotherapy; the MATISSE trial (NCT04620200). Neoadjuvant immunotherapy-response prediction via FDG-PET imaging was demonstrated feasible in the IMCISION trial (PMID 34937871), where a decrease of ≥12.5% in total-lesion glycolysis (TLG) upon immunotherapy identified deep pathological responders to immunotherapy in head and neck SCC prior to surgery with 95% accuracy. The current research investigates the predictive power of FDG-PET to identify deep pathological responses to neoadjuvant immunotherapy in MATISSE patients. Methods: 26 patients with primary CSCC (stage I‒IVa) were treated with neoadjuvant nivolumab with (n = 14) or without (n = 12) ipilimumab (weeks 0 and 2). FDG-PET/CT scans were evaluable at baseline and shortly before surgery (week 4) in 20 patients. Images were analysed for SUV_max, metabolic tumor volume (MTV), and TLG. Responders to immunotherapy were defined as having a major or partial pathological response to immunotherapy (MPR and PPR, showing ≤ 10% and 11-50% remaining viable cancer cells at time of surgery, respectively). Results: Overall, median SUV_max, MTV, and TLG decreased upon immunotherapy at the primary tumor site in responders (n = 15),whereas median SUV_max, MTV and TLG increased in non-responders (Table). Three patients with stable or increased SUV_max, MTV and TLG, also showed a pathological response and were classified as pseudo-progressive. Another patient with a MPR had an increase in SUV_max, but a decrease in MTV and TLG. All patients with any decline in SUV_max, MTV or TLG at the primary tumor site showed a pathological response (PPV 100%) and none of them developed a relapse at median follow-up 9.0 months. Conclusions: Primary tumor response assessment using FDG-PET-based ΔSUVmax, ΔMTV and ΔTLG accurately identifies pathological responses early upon neoadjuvant immunotherapy in cutaneous SCC. FDG-PET could, upon validation, select CSCC patients for response-driven treatment adaptation in future trials. FDG-PET-CT upon neoadjuvant immunotherapy in CSCC, changes in PET-parameters and predictive values of any decline in SUV_max, MTV or TLG. Clinical trial information: NCT04620200.

^a = p-values calculated with Mann-Whitney U test. PPV = positive predictive value, NPV = negative predictive value, Sens = sensitivity, Spec = specificity. *based on 13 responders and 4 non-responders.